The invention relates to substituted 4-phenyl-1-(1-phenylcyclohexyl)-1,2,3,6-tetrahydropyridines, a process for their production, medicaments containing these compounds, the use of these substances for the production of medicaments as well as method for treating pain using the medicaments.
Pain is one of the main symptoms in clinical practice, and there is a worldwide demand for effective pain treatment. The urgent practical need for a patient-oriented and targeted treatment of chronic and non-chronic painful conditions, which treatment in this context means the successful and satisfactory treatment of pain in patients, is documented in the large number of scientific articles that have recently appeared in the field of applied analgesics or in basic research on nociception. Thus, phencyclidine derivatives having an analgesic action are known for example from J. Med. Chem. 1981, 24, 469–499 and Arzneim.-Forsch./Drug Res. 44(II), No. 10 (1994), 1141–1144.
In WO 00/06545 compounds are described that have a high affinity for the nociceptin receptor ORL-1 and are likewise suitable for relieving pain.
Conventional opioids, such as morphine, are effective in treating severe to very severe pain. There are, however, numerous undesirable side effects including respiratory depression, vomiting, sedation, constipation as well as development of tolerance. Furthermore, they are less effective in treating neuropathic or incidental pain such as that which frequently occurs in patients with tumors.
Tramadol hydrochloride—(1RS,2RS)-2-[(dimethylamino)-methyl]-1-(3-methoxyphenyl)-cyclohexanol—occupies on the central nervous system, since this active substance is very effective in blocking pain without exhibiting the known side effects of opioids (J. Pharmacol. Exptl. Ther. 267, 33 (1993)).
Knowledge of the physiological importance of ion channel-selective substances has been obtained by the development of the patch-clamp technique. Of particular importance is the NMDA ion channel, through which a substantial proportion of synapse communications takes place. The exchange of calcium ions between a neuronal cell and its environment is controlled by this ion channel. The action of NMDA antagonists on the inflow of calcium ions into the cell interior has been detected by means of the patch-clamp technique.
In the unactivated state, the NMDA ion channels are in each case closed by individual magnesium ions that are located in the interior of the channel, and ions cannot pass through the channel due to their size. In the activated state the smaller calcium and sodium ions can pass through the channel. The (+)-MK801 binding site of the NMDA ion channel (ionotropic NMDA receptor) is also located in the interior of this membrane protein. Substances with an NMDA-antagonistic action, such as phencyclidine (PCP), ketamine or MK801, occupy this binding site (so-called channel blockers) and thus close the relevant NMDA ion channel.
NMDA ion channels play an important role in many physiological and pathophysiological processes, such as in epilepsy, schizophrenia, neurodegenerative diseases, in particular Alzheimer's disease, Huntington's disease and Parkinson's disease, cerebral ischaemias and infarcts, psychoses caused by raised amino acid levels, brain swellings, deficiency states of the central nervous system, in particular in hypoxia and anoxia, AIDS dementia, encephalomyelitis, Tourette's syndrome, perinatal asphyxia and tinnitus.
The object of the invention was accordingly to provide analgesically active substances that are suitable for treating severe pain, in particular for treating chronic and neuropathic pain. In this connection they should exhibit both a μ-agonistic agonistic and an NMDA-antagonistic action. Furthermore these active substances should have as few as possible of the side effects of opioid analgesics, such as nausea, vomiting, dependency, respiratory depression and constipation.
According to the invention this object is achieved by substituted 4-phenyl-1-(1-phenylcyclohexyl)-1,2,3,6-tetrahydropyridines of formula I. These compounds have an excellent analgesic action.
The invention accordingly provides substituted 4-phenyl-1-(1-phenylcyclohexyl)-1,2,3,6-tetrahydropyridines of formula I,
wherein R1 denotes C1–C5-alkyl (branched or unbranched), halogen (except 4-Cl), O—C1–C5-alkyl (branched or unbranched), S—C1–C5-alkyl (branched or unbranched), and/or their salts of physiologically compatible or acceptable acids.
In preferred compounds R1 denotes methyl, chlorine (except in the 4-position), fluorine, methoxy or methylsulfanyl.
Particularly preferred are the following substituted 4-phenyl-1-(1-phenylcyclohexyl)-1,2,3,6-tetrahydropyridines:
4-(2-fluorophenyl)-1-(1-phenylcyclohexyl)-1,2,3,6-tetrahydropyridine or the corresponding hydrochloride (1)
4-(3-fluorophenyl)-1-(1-phenylcyclohexyl)-1,2,3,6-tetrahydropyridine or the corresponding hydrochloride (2)
4-(4-fluorophenyl)-1-(1-phenylcyclohexyl)-1,2,3,6-tetrahydropyridine or the corresponding hydrochloride (3)
4-(2-methoxyphenyl)-1-(1-phenylcyclohexyl)-1,2,3,6-tetrahydropyridine or the corresponding hydrochloride (4)
4-(3-methoxyphenyl)-1-(1-phenylcyclohexyl)-1,2,3,6-tetrahydropyridine or the corresponding hydrochloride (5)
4-(4-methoxyphenyl)-1-(1-phenylcyclohexyl)-1,2,3,6-tetrahydropyridine or the corresponding hydrochloride (6)
4-(2-methylphenyl)-1-(1-phenylcyclohexyl)-1,2,3,6-tetrahydropyridine or the corresponding hydrochloride (7)
4-(3-methylphenyl)-1-(1-phenylcyclohexyl)-1,2,3,6-tetrahydropyridine or the corresponding hydrochloride (8)
4-(4-methylphenyl)-1-(1-phenylcyclohexyl)-1,2,3,6-tetrahydropyridine or the corresponding hydrochloride (9)
4-(2-methylsulfanylphenyl)-1-(1-phenylcyclohexyl)-1,2,3,6-tetrahydropyridine or the corresponding hydrochloride (10)
4-(2-chlorophenyl)-1-(1-phenylcyclohexyl)-1,2,3,6-tetrahydropyridine or the corresponding hydrochloride (11).
The invention also provides a process for the production of substituted 4-phenyl-1-(1-phenylcyclohexyl)-1,2,3,6-tetrahydropyridines of formula I, which may be variously substituted by R1.
The production of the compounds according to the invention is carried out in the following stages:
The enamine IV is formed from cyclohexanone II and 1,4-dioxa-8-aza-spiro[4.5]decane III.

The enamine IV is directly reacted further with phenylmagnesium halide V to form the amine VI:

The amine VI is hydrolyzed in a further stage and compound VII is precipitated as hydrochloride.

The hydrochloride VII is released to form the free base VIII, which is reacted with a Grignard reagent IX to form the compound X.

After precipitation of the compounds X as hydrochlorides XI, the latter can be reacted further with formic acid to form the compounds I according to the invention.

According to a particularly preferred variant of the preceding process, in stage 2, i.e. the Grignard reaction, the enamine IV is reacted further directly in the presence of ethereal HCl with phenylmagnesium halide V that was previously introduced, to form the amine VI, which can be obtained in a higher and more reproducible yield in this way than by the aforedescribed process.

A further preferred process variant is carried out as follows:
The aminonitrile XII is formed from cyclohexanone II and 1,4-dioxa-8-aza-spiro[4.5]decane III in the presence of potassium cyanide and hydrochloric acid.

The compound XII is reacted with phenyl Grignard reagents to form the amine VI.

The subsequent stages correspond to those of the previous reaction pathways.
The invention also provides a further process for the production of the substituted 4-phenyl-1-(1-phenylcyclohexyl)-1,2,3,6-tetrahydropyridines of formula I that may be variously substituted with R1, in which the compound XIV is first formed from N-tert.-butyloxycarbonyl-4-piperidone XIII and Grignard reagent IX:

The tert.-butyloxycarbonyl protective group is split off from the compound XIV with an acid, preferably HCl, HBr or HBr/glacial acetic acid or formic acid, with the elimination of water. The compound XV is thereby formed as the HCl salt:

Compound XV is reacted with titanium(IV) chloride and cyclohexanone II to form the corresponding enamine XVI:

The enamine XVI is reacted in the presence of trimethylchlorosilane or ethereal HCl with phenylmagnesium halide (preferably chloride or bromide).
The HCl salt of the resultant compound of formula I is then precipitated.

The compounds of formula I can be converted into their salts in a manner well known to those in the art using physiologically compatible acids, for example hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid and/or aspartic acid. The salt formation is preferably carried out in a solvent, for example diethyl ether, diisopropyl ether, alkyl esters of acetic acid, acetone, and/or 2-butanone. Trimethylchloro-silane in methyl ethyl ketone is furthermore suitable for the preparation of the hydrochlorides.
The substituted 4-phenyl-1-(1-phenylcyclohexyl)-1,2,3,6-tetrahydropyridines according to the invention of formula I are non-toxic and thus are suitable pharmaceutical active substances.
The invention furthermore provides medicaments containing as active substance at least one substituted 4-phenyl-1-(1-phenylcyclohexyl)-1,2,3,6-tetrahydropyridine of formula I, or at least a salt thereof of physiologically compatible acids.
The invention accordingly also provides for the use of at least one substituted 4-phenyl-1-(1-phenylcyclohexyl)-1,2,3,6-tetrahydropyridine of formula I and/or their salts of physiologically compatible acids for the production of medicaments to treat pain, epilepsy, and/or schizophrenia and/or neurodegenerative diseases, in particular Alzheimer's disease, Huntington's disease or Parkinson's disease, and/or cerebral ischaemias and/or cerebral infarcts and/or psychoses caused by raised amino acid levels and/or brain swellings and/or deficiency states of the central nervous system, in particular hypoxia and/or anoxia, and/or AIDS dementia and/or encephalomyelitis and/or Tourette's syndrome and/or perinatal asphyxia and/or tinnitus and/or for the prophylaxis of strokes.
For the preparation of corresponding pharmaceutical formulations there are used, in addition to at least one substituted 4-phenyl-1-(1-phenylcyclohexyl)-1,2,3,6-tetrahydropyridine of formula I, or a salt thereof, carrier materials, fillers, solvents, diluents, colorants and/or binders. The choice of auxiliary substances, as well as the amounts thereof to be used, depends on whether the medicament is to be administered orally, intravenously, intraperitoneally, intradermally, intramuscularly, intranasally, buccally or topically, for example in the treatment of infections of the skin, mucous membranes and eyes. For oral application, preparations in the form of tablets, sugar-coated pills, capsules, granules, drops, juices and syrups are suitable, while for parenteral, topical and inhalative application, solutions, suspensions, readily reconstitutable dry preparations as well as sprays are suitable. Compounds according to the invention of formula I in depot form, in dissolved form or in a plaster, optionally with the addition of agents promoting penetration of the skin, are suitable percutaneous application preparations. Orally or percutaneously usable preparation forms permit the delayed release of the compounds according to the invention of formula I.
The amount of active substance to be administered to a patient depends on the patient's weight, on the type of application, medical indications and severity of the condition. Normally 50 to 500 mg/kg body weight of at least one 4-phenyl-1-(1-phenylcyclohexyl)-1,2,3,6-tetrahydropyridine of formula I are administered.